Unethical uses of humans as research subjects represent appalling chapters in the history of medicine.1 To ensure that effective protections against such abuses continue to evolve and improve, it is essential to continue to learn from historical examples. Sadly, a new example has recently come to light.While conducting research on the Tuskegee study of untreated syphilis,2 Wellesley College Professor Susan Reverby recently reviewed the archived papers of John Cutler, a US Public Health Service (PHS) medical officer and a Tuskegee investigator. Instead of finding Tuskegee records, however, Reverby found the records of another unethical study. In this study, vulnerable populations in Guatemala—mentally incapacitated patients, prison inmates, sex workers, and soldiers—were intentionally exposed to sexually transmitted infections (syphilis, gonorrhea, and chancroid).The work was directed by Cutler and was done with the knowledge of his superiors, including then Surgeon General Thomas Parran Jr. Funded with a grant from the National Institute of Health (NIH) to the Pan American Sanitary Bureau (which became the executive arm of the Pan American Health Organization), the study was conducted in cooperation with Guatemalan investigators by the USPHS Venereal Disease Research Laboratory, which 10 years later became a part of the Centers for Disease Control and Prevention (CDC).As described by Reverby,3 the study's initial syphilis experiments used female sex workers, intentionally infected with Treponema pallidum, as a source of infection to male prison inmates. At that time, sex workers were allowed into Guatemalan prisons. When the rates of female-to-male transmission proved to be low, the research approach changed to the direct inoculation of prison inmates and patients in the Guatemalan mental hospital. Most inoculation experiments involved subcutaneous injection of T pallidum or exposure of the penile foreskin to infectious material. The majority of study subjects were treated with penicillin, although available study records do not document therapy or completion of therapy for all subjects and some received only partial treatment.4One study subject, a patient with a history of severe epilepsy, died of status epilepticus during treatment with penicillin. Although additional deaths occurred during the conduct of the study in the mental hospital, they were most likely related to the high rates of underlying disease, such as tuberculosis. The investigators provided some items for institutional support, such as anticonvulsant medications and refrigerators to store vaccines, and offered cigarettes as an incentive to study subjects. The archives provide no indication that individuals understood that they were participating in research.Most of the gonorrhea and chancroid experiments were conducted with Guatemalan soldiers. While the initial studies involved sexual contact of soldiers with female sex workers who had been infected with gonorrhea, subsequent subjects were infected through intraurethral inoculations of Neisseria gonorrhoeae and cutaneous inoculations of Haemophilus ducreyi, and then treated with penicillin and sulfathiazole, respectively.

Ethical ViolationsEthical violations in this study clearly include the following: (1) study subjects were members of vulnerable populations including institutionalized and mentally disabled persons, prison inmates, and soldiers (who could not give valid informed consent); (2) individuals were intentionally infected with pathogens that could cause serious illness; and (3) deception was used in conducting the experiments. Correspondence between the investigators and their superiors also recognized the unethical nature of the work. A letter from Cutler's supervisor, R. C. Arnold, written in 1948, notes that, "I am a bit, in fact more than a bit, leery of the experiment with the insane people. They can not give consent, do not know what is going on, and if some goody organization got wind of the work, they would raise a lot of smoke."4 The study was never published.Unfortunately, such studies were not rare at the time. For example, intentional infection of prison inmates with gonorrhea and syphilis was conducted in Terre Haute, Indiana, and Sing Sing prison, respectively.5-6

SafeguardsOver the past 60 years, regulations safeguarding humans participating in research have been enacted7 (Table). The Nuremberg Code, which articulated the requirement for voluntary consent of research participants, was issued in 1947, in response to Nazi human experimentation. The Declaration of Helsinki, the first international set of ethical principles for medical research involving human research participants, was adopted in 1964 by the World Medical Association. The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, created following the revelation of the Tuskegee study, issued the landmark Belmont Report on ethical principles and guidelines for research involving humans in 1979.8 In 1981, these guidelines were embodied in Health and Human Services (HHS) regulations to protect research participants (45 CFR 46).9 In 1991, Subpart A of these regulations ("The Common Rule") was adopted by an additional 16 federal agencies.

Table. Evolution of Human Subjects Research and GuidelinesCould such unethical studies happen today? For research funded or conducted by the US government, the answer is no. All federally funded research projects in which human participants are exposed to more than minimal risk must be reviewed by an institutional review board (IRB) before proceeding, and, as described in the Common Rule, must involve written, signed informed consent of research participants or their legally authorized representative (except in rare cases). Federal regulations instruct IRBs to be " . . . particularly cognizant of the special problems of research involving vulnerable populations such as children, prisoners, pregnant women, mentally disabled persons, or economically or educationally disadvantaged persons."9 For institutions violating these regulations, sanctions are imposed by the HHS Office for Human Research Protections. Furthermore, the HHS Office of Research Integrity takes administrative action against individual investigators for whom a determination of research misconduct has been made.As clinical research increases in volume and complexity and more frequently crosses country borders—often to reach the most affected populations—continued scrutiny of guidelines governing research involving human subjects remains critical. As technologies evolve, it is essential to continuously consider what new risks—physical, psychological, or informational—might be raised by research, and how investigators can best inform, engage, and protect research participants.While effective protections against unethical research continue to evolve across the world, the past exploitations of vulnerable populations, including the subjects of the study in Guatemala in the 1940s, are regrettable and deeply saddening. For them, the basic ethical principle of respect for persons was flagrantly violated. The NIH and CDC are committed to ensuring that lessons drawn from the past help shape actions to protect all future research participants, no matter where studies are conducted. The 1946-1948 inoculation study should never have happened, and nothing like it should ever happen again.